#SEOM20
Inmunoterapia en cáncer esófago-gastrico Fernando Rivera Herrero
Hospital Universitario Marqués de Valdecilla. IDIVAL. Santander
Disclosure Information
Consultant or Advisory Role: Roche, Merck-Serono, Amgen, MSD, BMS, Lilly, Celgene, Sanofi-Aventis, Servier, Astra-Zeneca, Bayer
Research Funding: Roche, Merck-Serono, Amgen, MSD, Lilly, Celgene, Sanofi-Aventis, Servier, Bayer
Speaking: Roche, Merck-Serono, Amgen, MSD, BMS, Lilly, Celgene, Sanofi-Aventis, Servier, Bayer
Grant support: Amgen
#SEOM20
Inmunoterapia en cáncer esófago-gástrico
GUION
.- Introducción
.- Cáncer esofágico
- E. Resecable
- E. Avanzada
.- Adenocarcinoma gástrico
- E. Resecable
- E. Avanzada
.- Conclusiones
Cáncer Esófago-Gástrico Grupo heterogéneo de enfermedades
Cáncer de esófago - Ca. Epidermoide
- Adenocarcinoma
Adenocarcinoma de la UEG
Adenoca. Gástrico
Gradations of molecular subtypes of gastro-esophageal carcinoma
The Cancer Genome Atlas Research Network. Nature 2017
#SEOM20
Inmunoterapia en cáncer esófago-gástrico
GUION
.- Introducción
.- Cáncer esofágico
- E. Resecable
- E. Avanzada
.- Adenocarcinoma gástrico
- E. Resecable
- E. Avanzada
.- Conclusiones
CheckMate 577
CheckMate 577 study design
7
• CheckMate 577 is a global, phase 3, randomized, double-blind, placebo-controlled triala
Placebo
Q2W × 16 weeks then Q4W
Key eligibility criteria
• Stage II/III EC/GEJC
• Adenocarcinoma or squamous cell
carcinoma
• Neoadjuvant CRT + surgical resection
(R0,b performed within 4-16 weeks
prior to randomization)
• Residual pathologic disease
– ≥ ypT1 or ≥ ypN1
• ECOG PS 0–1
Primary endpoint:
• DFSe
Secondary endpoints:
• OSf
• OS rate at 1, 2, and
3 years
R
2:1
Nivolumab
240 mg Q2W × 16 weeks
then 480 mg Q4W N = 794
n = 532
n = 262
Stratification factors
• Histology (squamous vs adenocarcinoma)
• Pathologic lymph node status (≥ ypN1 vs ypN0)
• Tumor cell PD-L1 expression (≥ 1% vs < 1%c)
Kelly RJ et al, ESMO 2020
Total treatment duration
of up to 1 yeard
• Median follow-up was 24.4 months (range, 6.2–44.9)g
• Geographical regions: Europe (38%), US and Canada (32%), Asia (13%), rest of the world (16%)
794 pts incluidos - 15% asiáticos - 29% C epidermoides - 40% UEG - 17% PDL1-TPS >1%
CheckMate 577
Disease-free survival
8
aPer investigator assessment; b6-month DFS rates were 72% (95% CI, 68-76) in the nivolumab arm and 63% (95% CI, 57-69) in the placebo arm; cThe boundary for statistical significance at the pre-specified interim analysis required the P value to be less than 0.036.
• Nivolumab provided superior DFS with a 31% reduction in the risk of recurrence or death and a doubling in median DFS versus placebo
Nivolumab
(n = 532)
Placebo
(n = 262)
Median DFS, mo 22.4 11.0
(95% CI) (16.6–34.0) (8.3–14.3)
HR (96.4% CI) 0.69 (0.56–0.86)
P value 0.0003c
Months 0 45 42 39 36 33 30 27 24 21 18 15 12 9 6 b 3
532 0 3 4 8 22 41 68 92 147 181 212 249 306
0 1 2 5 12 17 28 38 53 65 80 96 126
364 430
0
20
40
100
80
60
DFS
a (
%)
Nivolumab
Placebo
No. at risk
Placebo 262 214 163
Nivolumab
CheckMate 577
Disease-free survival by subgroups
9
• DFS favored nivolumab versus placebo across these pre-specified subgroups
Overall (N = 794) 22.4 11.0 0.70
Age, years < 65 (n = 507) 24.4 10.8 0.65 65 (n = 287) 17.0 13.9 0.80
Sex Male (n = 671) 21.4 11.1 0.73 Female (n = 123) Not reached 11.0 0.59
Race White (n = 648) 21.3 10.9 0.71 Asian (n = 117) 24.0 10.2 0.70
ECOG PS 0 (n = 464) 29.4 11.1 0.73 1 (n = 330) 17.0 10.9 0.66
Disease stage II (n = 278) 34.0 13.9 0.72 at initial diagnosis III (n = 514) 19.4 8.5 0.68
Tumor location EC (n = 462) 24.0 8.3 0.61 GEJC (n = 332) 22.4 20.6 0.87
Histology Adenocarcinoma (n = 563) 19.4 11.1 0.75 Squamous cell carcinoma (n = 230) 29.7 11.0 0.61
Pathologic lymph ypN0 (n = 336) 27.0 0.74 node status ypN1 (n = 457) 14.8 7.6 0.67
Tumor cell PD-L1 1% (n = 129) 19.7 14.1 0.75 expression < 1% (n = 570) 21.3 11.1 0.73
Indeterminate/nonevaluable (n = 95) 9.5 0.54
0.25
Nivolumab better Placebo better
4 1 0.5 2
Subgroup Nivolumab
Median DFS, months
Placebo Unstratified HR
Unstratified HR (95% CI)
Not reached
Not reached
CM-577 nivolumab adyuvante tras QT/RTCx en C esofágico resecado
10
Es un estudio claramente positivo
…pero con algunas DUDAS:
.- Mayor seguimiento y datos de Sv
.- ¿adenoca de la UEG?
.- Selección de pacientes
¿CPS en vez de TPS? ¿Otros BM: TMB …?
.- ¿Nivo tras QT/RT definitiva?, ¿o tras QT perioperatoria?
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Inmunoterapia en cáncer esófago-gástrico
GUION
.- Introducción
.- Cáncer esofágico
- E. Resecable
- E. Avanzada
.- Adenocarcinoma gástrico
- E. Resecable
- E. Avanzada
.- Conclusiones
Pembrolizumab en cáncer esofágico
628 pts incluidos - 39% asiáticos - 64% C epidermoides - 35% PDL1-CPS >10
3 obj primarios: - Sv ITT - Sv en C epidermoides - Sv en PDL1-CPS>10
1- Kojima et al. J Clin Oncol 2019
P. III KN 181 1: Pembro vs Chemo in 2nd line Esop.Cancer: Final Analysis
2nd line Advanced Esophageal Cancer: Pembrolizumab
628 pts 401 pts (64%)
222 pts (35%)
1- Kojima et al. J Clin Oncol 2019
prespecificado
p<0,0077
prespecificado
p<0,0077
prespecificado
p<0,0085
1- Kojima et al. J Clin Oncol 2019
P. III KN 181 1: Pembro vs Chemo in 2nd line Esop.Cancer: Final Analysis
2nd line Advanced Esophageal Cancer: Pembrolizumab
On July 30, 2019, the Food and Drug Administration approved pembrolizumab (KEYTRUDA, Merck) for patients with recurrent, locally advanced or metastatic, squamous cell carcinoma of the esophagus (ESCC) whose tumors express PD-L1 (Combined Positive Score [CPS] ≥10), as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy
17
P. III KN 590 1: Chemo-Pembro vs Chemo-pcb in 1st line Esop.Cancer
1st line Advanced Esophageal Cancer: CT+ Pembrolizumab
1- Kato et al. ESMO 2020
286 pts (38%) 548 pts (73%) 383 pts (51%) 749 pts
#SEOM20
Inmunoterapia en cáncer esófago-gástrico
GUION
.- Introducción
.- Cáncer esofágico
- E. Resecable
- E. Avanzada
.- Adenocarcinoma gástrico
- E. Resecable
- E. Avanzada
.- Conclusiones
MONEO Perioperative G/EGJ II FLOT + avelumab 40 DANTE Perioperative G/EGJ R II FLOT 295 DFS/PFS NCT03421288 FLOT + Atezolizumab
Selected Ongoing trials with Inmunotherapy in resectable G/EGJ Adenoca
EGJ: preop CT-RT
#SEOM20
Inmunoterapia en cáncer esófago-gástrico
GUION
.- Introducción
.- Cáncer esofágico
- E. Resecable
- E. Avanzada
.- Adenocarcinoma gástrico
- E. Resecable
- E. Avanzada
.- Conclusiones
Immuno Checkpoint Inh in AdGC
1st line manteinance 2nd line ≥ 3rd line
KN 059. Coh 1
ATTRACTION-02
Javelin 300
KN 061 KN 062
Pem
bro
lizum
ab
Niv
olu
mab
Ave
Promising P. II
Rand P. III +
Rand P. III -
Ongoing P III
KN 811
KN 859
Javelin 100 manteinance
ATTRACTION-04
CM 649
Nivolumab (Anti PD-1) A positive asian P III in refractory disease
1.- Lancet. 2017 Dec 2;390(10111):2461-2471
2- Kang YK, et al. ASCO-GI 2017 . Abst 1 ;
3.- Boku N et al, ESMO 2017
P. III ATTRACTION-02 / ONO-4538 1,2,3
Advanced Gastric cancer, refractory to standard therapy (> 2 lines)
493 pts (rand 2/1)
Placebo Nivolumab 3 mg/kg / 14 d Primary Endpoint:OS
Pembrolizumab (Anti PD-1) P II KEYNOTE 059 (Cohort 1: > 2nd line)
1- Fucks CS et al, JAMA Oncol, 2018
259 pts (PD-L1 + 57%; Asian 13% )
RR 12%, DC 27% Dur of Resp: 8.4 m
Higher activity in PD-L1 + CPS>1 vs CPS <1
RR: 15% 6%
Dur of Resp 16,3 m 6,9 m
1 y OS: 26%
Immuno Checkpoint Inh in AdGC
1st line manteinance 2nd line ≥ 3rd line
KN 059. Coh 1
ATTRACTION-02
Javelin 300
KN 061 KN 062
Pem
bro
lizum
ab
Niv
olu
mab
Ave
Promising P. II
Rand P. III +
Rand P. III -
Ongoing P III
KN 811
KN 859
Javelin 100 manteinance
ATTRACTION-04
CM 649
Pembrolizumab in 2nd line AGC A negative P III in 2nd line
1.- Fuchs CS. ASCO 2018
P. III KN 0611
2nd line Advanced Gastric canc
592 pts
Paclitaxel Pembrolizumab Primary Endpoint:
PFS and OS in PD-L1+ (CPS ≥1) OS (median) 9.1 m vs 8.3 m HR 0.82 (0.66-1.03 ) p 0.042 (0.0135)
PFS (median) 1.5 m vs 4.1 m HR 1.37 (1.03-1.57) p NS
P. III KN 0611,2
1.- Fuchs CS. ASCO 2018 2.- Fuchs CS, ASCO 2020
Overall Survival by PD-L1 (CPS)
33% of pts
67% of pts 18% of pts 29% of pts
P. III KN 061: tTMB predictive value 1
1.- Fuchs CS. ASCO 2020
- tTMB >175 in 18% of pts - predictive value of tTMB is independent of MSI-H and PDL1/CPS
Immuno Checkpoint Inh in AdGC
1st line manteinance 2nd line ≥ 3rd line
KN 059. Coh 1
ATTRACTION-02
Javelin 300
KN 061 KN 062
Pem
bro
lizum
ab
Niv
olu
mab
Ave
Promising P. II
Rand P. III +
Rand P. III -
Ongoing P III
KN 811
KN 859
Javelin 100 manteinance
ATTRACTION-04
CM 649
Avelumab (Anti PD-L1)
805 pts 499 pts
Primary endpoints: - OS in ITT pts - OS in PD-L1+
(TPS>1%
Moehler MH, et al. ASCO-GI-2020
Immuno Checkpoint Inh in AdGC
1st line manteinance 2nd line ≥ 3rd line
KN 059. Coh 1
ATTRACTION-02
Javelin 300
KN 061 KN 062
Pem
bro
lizum
ab
Niv
olu
mab
Ave
Promising P. II
Rand P. III +
Rand P. III -
Ongoing P III
KN 811
KN 859
Javelin 100 manteinance
ATTRACTION-04
CM 649
P III Pembrolizumab in 1st line AGC P. III KN 062
1st line Advanced G/EGJ canc
HER 2 -; PD-L1 + (CPS >1)
763 pts
1º endp.; OS/PFS in CPS>1 and CPS>10
Cisplatin-FU/X Placebo
Pembrolizumab Cisplatin-FU/X
Pembrolizumab
K Shitara et al, JAMA Oncol 2020
OS: P vs CT in CPS ≥ 1 .- Non inferiority demonstrated .- Superiority no demonstrated
OS: P vs CT in CPS ≥ 10 .- Superiority of P no tested …. But seems to be better with P
P III in 1st line AGC: QT+Anti-PD1 vs QT+Pcb: PFS P. III KN 062 1
HER 2 -;PD-L1 -CPS >1 (38% CPS>10)
Asian 25%,EGJ 30%, M1 95%
1º endp: OS/PFS in CPS>1, CPS>10
2L/3L Immuno in control arm: 15%
Cispl-FU/X Placebo
Pembro Cispl-FU/X Pembro
/X
1.- K Shitara et al, JAMA Oncol 2020;
507 pts
HR 0,84 p 0,03
(>p 0.001)
HR 0,73
P III in 1st line AGC: QT+Anti-PD1 vs QT+Pcb: PFS P. III KN 062 1
HER 2 -;PD-L1 -CPS >1 (38% CPS>10)
Asian 25%,EGJ 30%, M1 95%
1º endp: OS/PFS in CPS>1, CPS>10
2L/3L Immuno in control arm: 15%
Cispl-FU/X Placebo
Pembro Cispl-FU/X Pembro
/X
P. III CM 649 2
HER 2 -; PD-L1 + /- (60%CPS >5)
Asian 25.%, EGJ/EA 20%, M1 96%
1º endp: OS/PFS in CPS>5 (2º CPS>1, all pts)
2L/3L Immuno in control arm: 8%
FOLFOX/XELOX Placebo
Nivo.Ipi FOLFOX/XELOX Nivo
P. III ATTRACTION-04 3
HER 2 -; PD-L1 +/-
Asian 100% , EGJ 11%,
1º endp: PFS/OS
2L/3L Immuno in control arm: 27%
Oxali-X/S1 Placebo
Oxali-X/S1 Nivo /X
1.- K Shitara et al, JAMA Oncol 2020; 2.- M Moehler et al, ESMO 2020; 3.- Boku N et al, ESMO 2020
/X
1581 pts 507 pts 724 pts
HR 0,84 p 0,03
HR 0,73 HR 0,68 p 0,0001
HR 0,74 HR 0,77 HR 0,68 p 0,0007
CPS >1 CPS >10 CPS >5 CPS >1 All pts All pts
P III in 1st line AGC: QT+Anti-PD1 vs QT+Pcb: OS P. III KN 062 1
HER 2 -;PD-L1 -CPS >1 (38% CPS>10)
Asian 25%,EGJ 30%, M1 95%
1º endp: OS/PFS in CPS>1, CPS>10
2L/3L Immuno in control arm: 15%
Cispl-FU/X Placebo
Pembro Cispl-FU/X Pembro
/X
P. III CM 649 2
HER 2 -; PD-L1 + /- (60% CPS >5)
Asian 25.%, EGJ/EA 20%, M1 96%
1º endp: OS/PFS in CPS>5 (2º CPS>1, all pts)
2L/3L Immuno in control arm: 8%
FOLFOX/XELOX Placebo
Nivo.Ipi FOLFOX/XELOX Nivo
P. III ATTRACTION-04 3
HER 2 -; PD-L1 +/-
Asian 100% , EGJ 11%,
1º endp: PFS/OS
2L/3L Immuno in control arm: 27%
Oxali-X/S1 Placebo
Oxali-X/S1 Nivo /X
1.- K Shitara et al, JAMA Oncol 2020; 2.- M Moehler et al, ESMO 2020; 3.- Boku N et al, ESMO 2020
/X
1581 pts 507 pts 724 pts
HR 0,85 p NS
HR 0,85 P NS
HR 0,71 p 0,0001
HR 0,77 P 0,0001
HR 0,8 P 0,0002
HR 0,9 p 0,25
CPS >1 CPS >10 CPS >5 CPS >1 All pts
All pts
P III in 1st line AGC: QT+Anti-PD1 vs QT+Pcb: OS P. III KN 062 1
HER 2 -;PD-L1 -CPS >1 (38% CPS>10)
Asian 25%,EGJ 30%, M1 95%
1º endp: OS/PFS in CPS>1, CPS>10
2L/3L Immuno in control arm: 15%
Cispl-FU/X Placebo
Pembro Cispl-FU/X Pembro
/X
P. III CM 649 2
HER 2 -; PD-L1 + /- (60%CPS >5)
Asian 25.%, EGJ/EA 20%, M1 96%
1º endp: OS/PFS in CPS>5 (2º CPS>1, all pts)
2L/3L Immuno in control arm: 8%
FOLFOX/XELOX Placebo
Nivo.Ipi FOLFOX/XELOX Nivo
P. III ATTRACTION-04 3
HER 2 -; PD-L1 +/-
Asian 100% , EGJ 11%,
1º endp: PFS/OS
2L/3L Immuno in control arm: 27%
Oxali-X/S1 Placebo
Oxali-X/S1 Nivo /X
1.- K Shitara et al, JAMA Oncol 2020; 2.- M Moehler et al, ESMO 2020; 3.- Boku N et al, ESMO 2020
/X
1581 pts 507 pts 724 pts
HR 0,85 p NS
HR 0,85 P NS
HR 0,71 p 0,0001
HR 0,77 P 0,0001
HR 0,8 P 0,0002
HR 0,9 p 0,25
Ongoing P III Pembrolizumab in 1st line AGC
P. III KN 811
1st line Advanced G/EGJ C
HER 2 + 700 pts
CT-Herceptin
Pembrolizumab CT-Herceptin
P. III KN 859
1st line Advanced G/EGJ canc
HER 2 -; PD-L1 + (CPS >1) and -
1542 pts Platin-FU Placebo 1º Endpoint: OS / PFS
Platin-FU
Pembrolizumab
1º Endpoint: OS / PFS
P III KN-062 Pembrolizumab in 1st line AGC
MSI-H (7% of pts)
Shitara K , ESMO 2019
P III CM-649 Nivolumab in 1st line AGC
MSI-H (4% of pts)
Pembrolizumab in 1st line in MSI-H G/GEJC?
P III KN-062 Pembrolizumab in 1st line AGC
MSI-H (7% of pts)
Shitara K , ESMO 2019
P III CM-649 Nivolumab in 1st line AGC
MSI-H (4% of pts)
Pembrolizumab in 1st line in MSI-H G/GEJC?
P. III KN-177: Pembro vs CT in 1st line MSI_H mCRC
Andre T et al, ASCO 2020
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Inmunoterapia en cáncer esófago-gástrico
GUION
.- Introducción
.- Cáncer esofágico
- E. Resecable
- E. Avanzada
.- Adenocarcinoma gástrico
- E. Resecable
- E. Avanzada
.- Conclusiones
#SEOM20
Inmunoterapia en cáncer esófago-gástrico
CONCLUSIONES. Ca de esófago
.- Carcinoma epidermoide y adenocarcinoma de esófago son dos entidades muy distintas que deberían estudiarse por separado
.- Enf. Resecable: CM-577: papel de nivolumab adyuvante tras QT/RTCx
.- 2ª línea: KN-181: pembro aprobado por FDA para epidermoides + CPS>10
.- 1ª línea: KN -590: pembro+QT superior a QT (claro en CPS>10; más dudoso en CPS<10)
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Inmunoterapia en cáncer esófago-gástrico
CONCLUSIONES. Ca Gástrico .- En marcha estudios en enfermedad resecable
.- Enf refractaria: Nivo aprobado en Japón (ATTRACTION-2) y Pembro en CPS>1 por FDA (KN 059)
.- 2ª línea: Pembro fase III KN-061 negativo (pero posible beneficio en CPS>10, MSI-H y TMB alto)
.- En 1ª línea
- KN 062: Pembro equivalente a QT en CPS >1; posiblemente superior en CPS>10; menos tox
- antiPD-1+QT vs QT (KN-062, CM 649, ATTRACTION-4):
- KN 062 com pembro negativo (tendencia a mejor SLP y SV) F III en marcha
- CM-649: con Nivo mejor SLP y Sv en CPS>5 (posible beneficio pero menor en CPS<5)
- ATTRACTION-4: con Nivo mejor SLP pero no Sv (¿2-3L inmuno en 27% pts del control?)
.- En MSI-H posible papel de los anti PD1 en 1ª línea (¿monoterapia o combinados con QT?)
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